Rifaximin (compound identified by CAS registry number 80621-81-4) is a non-absorbable semisynthetic rifamycin antibiotic disclosed for the first time by Alfa Wasserman on 1981 (BE888895); this compound is currently utilized in therapy for the treatment of traveler's diarrhea and hepatic encephalopathy. Pharmacokinetics studies carried out on Rifaximin confirmed that this compound is not absorbed from the intestine to any significant amount (Cellai, L.; Cerrini, S.; Brufani, M.; Marchi, E.; Mascellani, G.; Montecchi, L. Structure-activity relationships in 4-deoxypyrido(1′,2′-1.2)imidazo(5.4-c) rifamycin SV derivatives. Chemioterapia (1983), 2(5. Suppl.: Mediterr. Congr. Chemother., Proc., 3rd, 1982), 53-4).
The structural formula of Rifaximin is the following

Due to this lack of systemic absorption Rifaximin has no application outside the gastrointestinal tract and has an excellent safety profile.
Literature data confirm that this substance may be isolated in different crystalline forms identified with the letters of the Greek alphabet: the α, β and γ forms were disclosed on 2004 (EP1557421 by Alfa Wasserman), the ε and δ forms on 2006 (EP1698630 by Alfa Wasserman), the ζ, η, α dry, ι forms on 2009 (WO2009108730 by Salix Pharmaceuticals, Ltd.), κ and θ forms on 2011 (WO2011153444 by Salix Pharmaceuticals, Ltd.). Moreover it is known that Rifaximin may exist in an amorphous form (WO2008035109 by Cipla Limited) and in an amorphous halo form (WO2011080691).
Rifaximin in the polymorphic form α (the crystalline form present on the market with the trade name of Xifaxan®) is considered a non-absorbable drug, however the results of more recent pharmacological studies (see for example G. C. Viscomi et al. Crystal forms of Rifaximin and their effect on pharmaceutical properties Cryst Eng Comm, 2008. 10. 1074-1081) suggest that some of the above listed crystalline forms, for example the γ and the δ forms could be significantly absorbed.
Moreover, the above cited literature data indicate that the known polymorphic forms of Rifaximin may easily change their polymorphic form if exposed to different values of relative humidity: for example the anhydrous α- and δ-forms can be obtained by drying the monohydrate β-form at different temperatures (30-65° C.) under vacuum and the anhydrous α form can be transformed into the corresponding monohydrate β form at a relative humidity of 56% after 40 hours (EP 1557421).
The present inventors found that in particular the crystallization and drying conditions (using traditional static or dynamic drier, like a biconical drier) described in EP 1557421 showed to be critical since they did not consistently afford the desired α or α/β mixtures but the undesired γ polymorphic form or other polymorphic mixtures.
The control of the obtained solid state of Rifaximin polymorphic forms is usually performed by DRX spectroscopy, since the traditional differential calorimetry analysis (DSC) and infrared spectroscopy (IR) are not able to discriminate and to quantify these polymorphs; also the water content, as determined by Karl-Fisher, can give only indirect information on the solid state since cannot discriminate between adsorbed water and water in the lattice. Moreover, more than one hydrate and anhydrous forms for Rifaximin have been described.
The conversion of these polymorphic forms is therefore critical and need to be taken into account in order to guarantee the “consistency” of the crystalline form in the Active Pharmaceutical Ingredient (API) and in the drug product (Guidance for Industry ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2007).
It should be pointed out that the “consistency”, namely the reproducibility of the polymorphic form, is very important, especially in view of the regulatory requirements.
Finally, also for the preparation of the drug product the stability of the polymorphic forms of Rifaximin (for example film coated tablets) is critical. The present inventors have experimental evidence that the wet granulation procedures and tableting might modify the initial solid state of this API: for example the wet granulation procedure of Rifaximin α form, a procedure that provides the use of purified water as binding agent, afforded a sensible amount of Rifaximin β form (<50%) as result of a change in the solid state of this API from anhydrous (α form) to hydrate (β form).
These findings indicate the need of putting appropriate manufacturing procedures in place to consistently yield Rifaximin of the appropriate solid state suitable to minimize changes of the solid state during the preparation of the drug product.